TAP CHI NGHIEN CU'U Y HOC •
LIEN QUAN GIU'A NONG DO GLUCAGON - LIKE PEPTIDE - 1 V a i BIEN CHU'NG THAN & BENH NHAN DAI THAO DLPaNG
TUPE 2 CHAN DOAN L A N DAU
Le Dinh Tuan', Nguyin Thj Phi Nga^, Trln Thj Thanh Hoa' 'Trwong Dai hoc Y Dwoc Thai Binh; ^Hoc vien QuSn Y
^Benh vi^n NQi ti§t Trung wong
Nghien cuv tnen khai tren 160 benh nhan dai thao duong type 2 chin doan iin diu tai Benh vien Noi bit Tiung uong nhSm tim hiiu moi lien quan giwa ndng do glucagon - like peptide • 1 vdi vai biSn chimg than Kit qua cho thay ty le benh nhan co microalbunvn ni^u (MAU) f+J 7,5%, macroalbumin nieu (MAC) (+)- 13,1%, co bien chimg than 20,6% Nong 66 trung binh GLP - 1 a benh nhan co bien chimg than (6,10 ± 3,71 pmolA) thap hon so v&i nhom benh nhan khong co bi§n chung than (7,58 ± 3,65 pmoi/l. p < 0,05) Ty ie b$nh nhan giam ndng d^ GLP - 1 a nhom co bien chu'ng than cao han 2,24 ian so vdi nhom khong co bien chimg than (p < 0,05) Phan tich da bien cho thay tang nong do MAU co lien quan vai giam nong dO GLP - 1 va tang glucose mau khi doi (p < 0.05). O benh nhan dai thao dwong type 2 chin doan Ian 6iu. co mdi lien quan giu-a ndng d p glucagon - like peptide - 1 vcri bien chimg th$n
TiF khoa: dai thao du'dng typ 2, giucagon-like peptide-1, bien chieng than
I.
DAT
V A NBt
Benh than dai thao dyang la nguyen nhan hang dau cua eac tryo'ng hap suy than man giai doan c u l i a cac nude chau Au, Nhat Ban va Hoa Ky, xay ra khoang 40% a dai thao duang type 2 tuy theo chung toe [1] Mdt nghien cuu io-n da khang dmh ganh nang benh than dai thao dydng type 2 d' eae nyo'c Nam A nhi§u ban so vd'i chau Au, nghien ciKU ghi nhan tan suit t i l u dam vi the a benh nhan cac nydc Nam A cao ban 1,2 - 1,7 lan so vdi chau Au. Cac nghien eifu ghi nhan tai thai diem chan doan da cd bi^n chung than, nSu khong duac di^u tri se diln tiSn ddn suy than man [1; 2]. Glucagon - like peptide -1 (GLP
Dia chi Ii4n h$. Le Binh Tuan. Trudng Dai hgc Y Duoc Thai Binh
Email letuan985@gmail com Ngaynhan 03/01/2017 Ngay auoc chap thuan 25/4/2017
1) la mot thanh vien ca ban ciia incretin, duoc phat hien vao dau nhO'ng nam 1980 GLP - 1 la mot peptide cd 30/31 acid amin, dygc tong hop va bai tidt bai t^ bao L, cae t^ bao nay cd chii yeu a dean cu6i hdi trang va dai trang [3 - 5] GLP - 1 kich thich bai tiat insulin va ifc cha bai t i i t glucagon sau an do vay lam giam glucose mau GLP - 1 kich thich tuy tai sinh va tang sinh, ehdng tai s y chat theo chuong tnnh ciia ta bao p, dong thai GLP - 1 cdn cd tac dung ehdng xa vifa mach mau, bao ve than kinh, bao ve tim, bao ve than [6, 7] , Receptor GLP - 1 truyfen thdng tin ciia mRNA dyac phat hien tai tieu c l u than va tren cac t§ bao noi mac mach mau tieu c l u than, do dd GLP - 1 CO nhilu tac dung sinh hoc tren than G i n day nhieu nghien eifu thyc hien da ehicng minh anh hydng eiia GLP - 1, cae chat ddng van thu the GLP - i , chat ii'c e h l DPP - 4 din chirc nang than, chiing ddng vai trd nhy la bien phap hij'u hieu dilu tn cac biln chimg
TCNCYH 107 (2)-2017
• TAP CHi NGHIEN CU'U Y HOC than a benh nhan dai thao dyd'ng [8'-10] Tai
Viet Nam hien chya ed d l tai nghien ciru nao d l cap d i n m i l hen quan giua ndng dd GLP-1 vai biln chirng than. Vi vay, d l tai nay duac tiln hanh vdi muc heu Tim hilu mdi lien quan giua nIng do GLP - 1 vai biln chieng than d' benh nhan dai thao dydng type 2 chan doan lln d l u .
II. E)6l TU-aNG VA PHU'aNG PHAP
I . D o i tu'O'ng
G i m 160 benh nhan dai thao dyd'ng type 2 ehln doan l l n d l u kham va dieu tri tai Benh vipn NOI tilt Trung yang Thd'i gian nghien e y u t y thang 12/2014 d i n thang 12/2016
Tigu chuan ehln doan dai thao dudng theo ADA nam 2012 [11] Chan dean dai thao dudng type 2 theo WHO 1999 van dung phu hgp vdi d i l u kien Viet Nam [1j
- Tieu chuan ioai t<hdi nghien ciru + Benh nhan dai thao dydng type 1, dai thao dudng type 2 da duac dilu tn blng thulc nhdm ddng van thu t h i GLP - 1 hoac ire ehl D P P - 4
+ Benh nhan dang co tinh trang benh nang hon me, tien hon me, ha dydng huylt, can tang huylt ap kich phat, lao, viem phdi, HIV, viem gan
+ Benh nhan dang d i l u tn cac benh than man tinh va viem than b l than trydc khi phat hien dai thao dydng, suy than giai doan nang (III, IV).
+ Benh nhan thilu mau nang, can dau that nguc khong I n dmh, tai b i l n mach mau nao, nhli mau ca tim, suy kiet, rdi loan tam t h i n
+ Benh nhan da p h l u thuat I n g tieu hda, dang d i l u tri cac benh I n g tieu hoa trudc khi
nhap vien, dang dieu tn ung thu, nghien ryau.
+ Benh nhan khdng hgp tac, khdng thu thap du chi tieu nghign cyu
2. Phu'ang phap: tien ciru, md ta e l t ngang
- Phyang phap ehon mSu
+ each chon m l u chon mSu cd chii dich -*• C d m l u chon mau toan bo vdi n - 160 (benh nhan)
- Ndi dung nghien ciru
Kham lam sang, tudi, gidi, n g h i nghiep, tiln sy ban than va gia dinh Kham toan dien cac ea quan ho hap, tuan hoan, tieu hoa, tiet nieu.
Can lam sang va tham do chifc nang cac chf s i sinh hoa mau ca ban. glucose mau, HbAlc, C - peptid, ure, creatmm, MAC, MAU Cac xet nghiem dyac thuc hien tai Khoa Sinh hoa - Benh vien Ndi tilt Trung yang
+ Omh luang hocmon GLP-1 lly mau tinh mach khi ddi (nhin an it nhlt 8 gid)
Nguyen ly dya tren phan u'ng dac hieu giCra khang the dugc g i n d day gilng ELISA vdi khang nguyen GLP - 1 co trong huylt thanh cua benh nhan, k i t hap vdi su chuyin mau eua ea ehlt dac hieu trong phan yng ELISA, do mau d may p h i quang k l co bydc sdng 450 nm Don vi tinh pmol/l
Nai tien hanh Trung tam Sinh hoe Phan tip Y Dyac hoc Quan sy - Hoc vien Quan Y
+ Dmh lyang albumin nieu dai the (MAC) lly 10ml nydc t i l u (giya bai) buoi sang Dinh luang b l n g ky thuat quang pho so mau (xet nghiem nydc t i l u 10 thong s i ) duoc thue hien tren may Beckman Coulter AU2700 MAC (+)khi >300mg/l[12}-
TAP CHi NGHIEN CLPU Y HOC - + Dinh luang albumin nieu vi the (MAU).
tien hanh lam xet nghiem dmh luang MAU d benh nhan ed MAC (-) lly 5ml nude t i l u (giu'a bai) bull sang, Dmh luang blng ky thuat do dp due miln dich, MAU (+) khi > 30 mg/lva<300mg/l[12],
+ Giam mire loc c l u than, khi mii'C loc e l u than < 60 (ml/ph). U'dc tinh muc loc elu than blng theo cdng thirc Cockcroft va Gault [12]
+ Biln chirng than khi benh nhan dai thao dudng type 2 cd mot trong cac tneu chung sau MAU (+) hoac MAC (+) hoac giam mire loc c l u than,
- Xy ly s6 lieu blng phIn m I m SPSS 16 0 Gia tri trung binh ± do lech chuan dyae ap dung d l i vdi biln dmh luang hoac dydi dang tl le % hay t i n suit vdi biln dmh tinh Mire y nghla thing ke dyae tinh d mire 95% hoac 99%, khoang tin cay cung duae tinh trong
khoang 95% hoae 99% Phan tich dan bien SU' dung kiem dinh ANOVA so sanh gia trj trung binh d l i vdi cac b i l n dinh lugng, si>
dung kilm dinh yj so sanh ty la % d l i vdi cac biln dinh tinh. Dung he s i tuang quan "r" de tim moi tyang quan giQ'a hai bien. Tinh ty suit chenh OR (Odds Ratio) khi p < 0,05
3. Dao dire nghien c i i u
Benh nhan dyge kham chan doan dai thao dydng type 2 theo dimg khuyin cao.' dyoc giai thieh va d i n g y lam xet nghiem dinh lyang hormone GLP 1 (mien phi) Nghien CLFU duac Ban Giam doe B§nh vien, cac Khoa phong lien quan eiia Benh vien Ndi tilt Trung yang d i n g y cho phep thyc hien K i t qua xet nghiem ehi n h l m phuc vu nghien ciru khoa hoc chin doan va d i l u tn T i t ca cac thdng tin v l ngudi benh dygc giu bi mat tuyet dli
III.
KET QUABang 1. Dac diem ve ddi tu-gng nghien ciPu Chi tieu
TUOI trung binli (nam) Glucose mau kill aoi (mmol/l) HbAlc(%)
Ure (mmol/l) Creatinin (|jmol/l) GLP - 1 (pmoi;l)
Nam NO-
S6 lico'ng (n 86 74
= 160)
55,13 ± 10,50 12,21 ±4,45
9,74 ±2,58 5,53 ± 1,49 77,02 ± 13,56
7,27 ±3,70 Ty le (%)
53,3 46,2
Ty le benh nhan nam cao ban nu (53,8%), nong do GLP - 1 trung binh la 7,27 ± 3,70 pmol/l.
TCNCYH 107 (2)-2017'
• TAP CHI NGHIEN CU'U Y HOC Bang 2. Dac di&m ve bien chijng than
Chi tieu IVIAC (+)
MAU (+)
Giam miFC loc c l u tii^n Bien chLpng than
S6 lu'O'ng (n 21 12 0 33
= 160) Ty le (%) 13,1
7,5 0,0 20,6 Tyle b?nh nhan co MAU (+)• (13,1%), co biln chirng than. 20,6%.
Bang 3. Mdi lien quan giija nong do GLP - 1 vd'i albumin nieu va biln chu'ng than
Chi tieu
G L P - 1 (pmol/l) (n = 160) Trung binh Ty le giam
Bien ehipng than
IMAU (+) (n = 12) MAC(+)(n = 21)
P Co (n = 33) Khong(n =127)
P
4,56 ±2,62 6,98 ±4.00
>0,05 6,10 ±3,71 7,58 ± 3,65
<0,01
10(83,3) 15(71,4)
>0,05 25(75,8) 74 (58,3)
<0,05 OR OR = 2,24; 95%CI (0,94 - 5,35)
- N6ng do trung binh GLP - 1 giam a benh nhan co bien chung than so voi nhom benh nhan khong cb bi^n chu'ng than
- Ty le benh nhan giam GLP - 1 a nhom cb bibn chung than cao han 2,24 l&n so vai nhom khong co b i l n chirng than (p < 0,05)
350 300 250 5 200 o
I 150 -
T 100
y - - 3 5367X+ 47,024- R' = 0,0323
KIAU lmg;i)
Bi§u d6 1. Moi tu'O'ng quan giu'a n6ng do GLP - 1 va MAU
TAP CHI NGHIEN CU'U Y HQC — ^ — ^ ^ ^ — ^ — — ^ — ^ ^ ^ ^ - ^ ^ ^ ^ — — Ndng dd GLP - 1 khi ddi eo moi tyang quan nghich mifc do vCca vdi chi so MAU (r = -0,304;
p < 0,05)
Bang 4. Tu'O'ng quan hdi qui logistics da bien giCPa ndng do GLP - 1 khi doi, glucose mau khi doi, BMI, tu6i va CRPhs vdi MAU
Mo hinh CRPhs (mg/l) GLP - 1 (pmol/l) Glucose mau khi doi (mmol/l) Bl«l (kg/m^)
Tuoi H§ng so
Hesd p 0,027 -0,466 0,198 -0,035 -0,024 -0,590
SE 0,034 0,186 0,077 0,122 0,035
P
>0,05
<0,05
<0,0S
>0,05
>0,05
0 benh nhan dai thao dudng type 2, nIng do khi ddi GLP - 1 giam, tang gluocse mau khi ddi hen quan cd y nghTa thing kg d i n su tang MAU nieu (p < 0,05)
VI. BAN LUAN
Ton thyang than do dai thao dudng la biln chirng gap vdi ty le cao t y 20 - 40% Hau qua cull ciing la suy than man tinh giai doan c u l l [2] Suy giam chice nang than lam nang them tinh trang rdi loan ndi mdi, roi loan chuyen hda va nang them cac biln chieng khac Tai Viet Nam, mdt s6 nghien cieu cdng bd thly ty Ig biln ehdng than eua dai thao dydng kha eae tCr 22,7 - 38,9% [1], K i t qua nghien cuu cho thay benh nhan ngay tai thdi d i l m duac chan doan dai thao dydng ed biln ehdng than la 20,6%, ty le MAU dyang tinh la 7,5% Ket qua nghien ciru khae tai Benh vien Ndi tilt nam 2011 tren benh nhan dai thao dudng type 2 mdi chan doan cung cho thly ty le benh nhan eo MAU duang tinh la 26,0% [12, 13] Nhu vay, ngay tie khi mdi chan doan dai thao dudng da xult hien biln chifng than vdi ty le kha cao, vi vay, trong thye hanh lam sang c l n chu y de Iya chon phyang phap d i l u tri thich
hop nhlhn ngan chan s y phat trien cua biln chO-ng trong tyang lai...
Ket qua nghien ciru cho thay nIng do GLP 1 cd tyang quan nghich mire dd vira vdi MAU nieu O" benh nhan co biln chieng than nIng dd GLP - 1 t h l p han cd y nghTa thong ke so vdi benh nhan khdng cd biln chung than (p < 0,05). Khi phan tich hdi qui logictic da biln bao gom cac y l u t l ' CRPhs, GLP • 1.
glucose mau khi ddi, BMI, tuoi vdi su xult hian MAU thly sy x u l t hi^n MAU nieu cd li§n quan vdi tang glucose mau khi ddi va giam ndng do GLP - 1
Receptor GLP 1 truyin thdng tin eiia mRNA dyac phat hien tai t i l u e l u than va tr§n cac t l bao ndi mac mach mau t i l u eau than, vi vay GLP - 1 ed tac dung sinh hoc tren than.
Nhilu nghien eifu eho thay d benh nhan dai thao dydng type 2 cd s y suy giam bai tilt GLP - 1 , nIng do GLP - 1 mau thlp eo lien quan tdi
30 TCNCYH 107 (2)-2017
• TAP CHI NGHIEN CU'U Y HOC cac ton thyang tai e l u than nhy: xult hien
albumin nieu nguygn nhan cd the do suy giam ca c h i bao ve eiia c l u than [6] G i n day eae nghien ciru da ehdng mmh anh hydng cua GLP - 1, eae ehlt d i n g vSn thu the GLP - 1, chit uc che DPP - 4 den cac r l i loan chye nang c l u than va nhan thly GLP-1 ddng vai trd nhu la bien phap hu'u hieu d i l u tn cac biln chieng than Tren cac con chuot bi dai thao dudng duae d i l u tn b l n g exendin - 4, thly giam dyac albumin nieu, md rdng chat keo nin giya eae t l bao tieu c l u than, giam viem tilu c l u than, lam giam sa bdc Idc ciia yeu td biln d l i tang trydng (transforming growth fac- tor TGF - p i ) , loai bo ehlt collagen type - 4, giam sy xam nhap eua dai thuc bao, ehdng lai su ehlt theo chuong trinh tai tieu elu than va ehdng lai su phi dai cua t i l u c l u than [6]
Nghien cuu nam 2011 chieng mmh GLP 1 cdn lam giam cac marker h i p d i n su xam nhap cua dai thue bao trong md than, giam nIng do ICAM - 1, loai bo c h i t collagen type - 4, ching stress oxi hoa va sy kich hoat NF - kB [7] Ddng thdi ngan chan san xult cac cytokin ciia phan irng viem duoc kich thich bai tilt bdi tinh trang tang glucose mau nhu TNF - a, IL - 1p tai cac t l bao baeh eau mono THP - 1 va t l bao ndi mac ciia t i l u eau than Tuong tu, tac gia Hendarto va edng su nam 2012 nhan thly, thdng qua lam tang hoat tinh sinh hoc ciia GLP - 1, liraglutide binh thuang hda ndng do cae ehlt marker cua stress oxy hda, 8 - hydroxydeoxyguanosm, malonciialde- hyte, sy bdc Id ciia nicotinamide adenine dinu- cleotide phosphate oxidase, cac phan ty TGF - p i tai md than, lam giam albumin nieu [10]
Chit uc c h i DPP - 4, vildagliphn lam tang nong do GLP - 1 mau, do do cai thien do thanh thai creatmm, ire e h l su thay doi md hoe to ehue ke c l u than, iec che sy xa hoa t l
chyc e l u than, tec che su day mang day eau than theo phyang thiee phu thudc lilu Tac dung bao ve than ciia GLP - 1 cdn thdng qua ye e h l sy san xuat y l u t l ciia qua trinh viem TGF - p i , tai tydi mau viing t i n thuang c l u than bl thilu mau GLP - 1 cai thien cac ton thyang than thong qua tac ddng len tilu c l u than, ong than, cae ton thuang mach mau c l u than va cai thien tinh trang r l i loan lipid mau [7, 8],
V. K^T LUAN
Qua nghien cyu 160 benh nhan dai thao dudng type 2 chin doan Ian dau tai Benh vien NOI tilt Trung yang riit ra mot so ket luan sau
Ty le benh nhan cd MAU (+) la 7,5%, MAC(+)ia 13,1%. biln chieng than la 20,6%,
- Ning do trung binh GLP - 1 d benh nhan cd biln chieng than (6,10 ± 3,71 pmol/l) thap han so vdi nhdm benh nhan khdng cd biln chung than (7,58 ± 3,65 pmoi/l, p < 0,05)
- Ty le benh nhan giam GLP - 1 d nhdm cd biln chyng than cao han 2,24 lln so vdi nhdm khdng ed biln ehdng than (p < 0,05)
- Phan tich da bien cho thly sy xuat hien MAU nieu cd li&n quan vdi giam ndng do GLP - 1 va tang glucose mau khi doi (p < 0,05)
Levi c a m o r i
Nhdm nghian cdu xin tran trong cam an su giiip dd, hap tac nhiet tinh cua t i t ca benh nhan va ngudi nha benh nhan da tham gia nghien cdu. Xin gui Idi cam an ehan thanh d i n Ban Giam ddc, cac Khoa Lam sang, Khoa Hda sinh, cac Phdng Ban tai Benh vien Ndi t i l t Trung U'ang, Khoa Vi sinh Y hoc - Trung tam Sinh hoc Phan t d Y Dyac hoe Quan sy - Hoe vien Quan Y da tao moi dilu kien thuan
TAP CHi NGHIEN CU'U Y HOC lo'i, giiip dd de nghidn cuu duac thyc hign va hoan thanh.
TAI LIEU THAWI KHAO
1. Nguyin Thy Khue, Wlai Th^ Trach (2003). Benh dai thao dydng Ndi tilt hoc dai cuang Nha xuBt ban thanh phd Hd Chi Minh, 335 - 400
2. D6 Trung Quan (2013). Dai thao dudng Benh Ndi tiet chuyin hda. Nh^ xuit ban Gi^o due Viet Nam, 268 - 298.
3. Hoist Jens Juul (2007). The physiology of glueagon-like peptide -^.Physiol Rev, 87, 1400-1437
4. Liza Phillips K., Johannes PrinsB (2012). Update on mcrehn hormons Ann N Y Acad Sci, 0077 - 8923, 0 - 20
6. Jonhn Ussher., Daniel Drucker (2012).
Cardiovascular biology of the meretin system,FndocrRei/, 33(2), 187-215
6. Karoline von Websky, Christoph Reichtzeder et al (2014). Physiology and pathophysiology of mcretm in the kidney, Curr Opin Nephrol Hypertens, 23(1), 54 - 60
7. Kodera R., Shtkata K., Kataoka HU et al (2011). Gucagon-like peptide-1 receptor agonist ameliorates renal injury through its anti
-inflammatory action without lowering blood glucose level in a rat model of type 1 diabetes Diabetoiogia. 54, 1 - 1 2
8. Liu WJ., Xie SH., Liu YN et al (2012).
Dipeptidyl peptidase IV inhibitor attenuates kidney injury in streptozotoem-mdueed diabetic rats J Pharmacol Exp Ther, 340, 248 - 255
9. Jingjing Li., Meiping Guan and Chenzhong Li (2014). The DPP - 4 inhibitor sitagliptin protects against dyslipidenia-relafed kidney injury in Apolipoprotem E knockout Mice Int J Moi Sci, 15, 11416 -11434
10. Hendarto H., Inoguchi T., Wlaeda Y et a) (2012). GLP - 1 analog liragluhde protects against oxidative stress and albuminuna in streptozotoem-mdueed diabetic rats via protein kinase A-mediated inhibition of renal NAD(P)H oxidases. Metabolism, 51, 1422 -1434
11. American diabetes association(ADA) (2012). Standards of Medical Care in Diabetes -2012 D/aibetes Care, 35(1), S 1 1 - 8 6 3
12. Ha Hoang Kiem (2010). Than hoc lam sang Nha xuSt ban Y hoc, ISO-2^0
13. Nguyin Thu Thao (2011). Nghien ciru dae diem lam sang tren benh nhan dai thao dydng typ 2 mdi chan doan Tap chi Y hoc Thi/chinh, 12(789). 110-114
Summary
THE RELATIONSHIP BETWEEN GLUCAGON - LIKE PEPTIDE -1 CONCENTRATION AND KIDNEY COMPLCATIONS IN PATIENTS WITH
FIRST TIME DIAGNOSED TYPE 2 DIABETES MELLITUS
Our study was Carried out on 160 patients with firt time diagnosed type 2 diabetes mellitus (f2DM) in National Endocrinology Hospital to determine the relationship between fasting glucagon -like peptide - 1 (fGLP - 1) concentration and diabetic nephropathy m patients with f2DM The results showed that the percentage of mieroalbummuna (MAU) (+) was 7 5%, macroalbuminuna (MAC) (+) was 13 1% and renal complications was 20.6% In patients with renal complications, the average concentration of fGLP - 1 was lower than in patients without these complications (6 10 ± 3 71 vs 7 58 ± 3,65 pmol/l, respectively, p < 0.05). The prevalence of decreased fGLP - 1 was 2,24 times as much as the patients without kidney complications (p < 0 05) In the
32
TCNCYH 107 (2)-2017— . ^ ^ - ^ - ^ — . ^ ^ ^ ^ ^ ^ _ ^ ^ . ^ _ - TAP cHl NGHIEN CU'U Y HOC multivariate analysis model, the elevated of MAU had effected significantly on decreased GLP - 1 and hyperglycemia (p < 0 05), In conclusions, there were relationship between fGLP - 1 and kidney complications in the f2DM (p < 0.05)
Keywords: type 2 diabetes, glucagon - like peptide - 1 , kidney complications
